Advances in HAART have been a huge success story in the management of HIV infection and have significantly increased mean survival time. However, serious metabolic complications including osteoporosis and bone fractures are now becoming increasingly common and the responsible mechanisms remain poorly elucidated. Furthermore, whether osteoporosis stems from direct effects of HIV proteins on cellular metabolism, as a consequence of disease amelioration following application of pharmacological agents, or due to direct toxic effects of HAART on bone cells or other tissues regulating bone cells remains controversial. The skeleton continually regenerates through homeostatic bone remodeling, a process involving the removal of worn bone and reformation of new bone. Osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-:B (RANKL). The osteoclastogenic and proresorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). In both humans and animals any increase in the ratio of RANKL to OPG accelerates the rate of osteoclastic bone resorption leading to osteoporosis. The depth of integration between the immune and skeletal systems has only recently begun to be appreciated. While many cell types are capable of making RANKL and OPG we recently reported that in rodents in vivo, cells of the B lymphocyte lineage, under the control of costimulatory signalsmediated by T cells account for up to 64% of total bone marrow OPG concentrations, with mature B cells accounting for 45% alone. Consequently, B cells are critical stabilizers of peak BMD in vivo. Our preliminary studies have now demonstrated that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed in human patients. Furthermore, we found that B cell expression of OPG is significantly downregulated, concurrent with a significant upregulation in production of RANKL. We hypothesize that immunological disruption of B cell number and/or function, may play a key causal role in the bone loss associated with HIV/AIDS, by driving a switch from OPG production to overproduction of RANKL. In this study we propose two preclinical animal Specific Aims and two translational Specific Aims in humans to comprehensively determine the role of perturbations in B and T cells and the direct and indirect actions of HAART on OPG and RANKL production and on bone turnover. With the mean survival time for HIV-infected individuals continuing to rise, identifying, and responding to the root causes of altered bone metabolism in HIV/AIDS patients is of critical importance to minimize damage to the skeleton due to AIDS and/or HAART if we are to stem an epidemic of osteoporosis and bone fractures among AIDS patients in the future, as age associated declines in BMD exacerbate an already impoverished skeleton. PUBLIC HEALTH RELEVANCE: Osteoporosis and bone fractures are well established complications of HIV/AIDS, but the mechanisms remain poorly defined. This proposal will investigate how HIV-induced perturbations in B cell function drives bone loss in HIV/AIDS, and examine the effects of different HAART formulations on this process, in animals and humans.